US7087641B2ExpiredUtilityPatentIndex 71
4β-1″-[(2″-substituted benzoyl) anilino]podophyllotoxin analogues useful as anticancer agents
Est. expiryMar 28, 2022(expired)· nominal 20-yr term from priority
C07D 493/04A61P 35/00
71
PatentIndex Score
8
Cited by
7
References
21
Claims
Abstract
The present invention provides a new class of compounds 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin exhibiting anti cancer activity and a process for preparing the same.
Claims
exact text as granted — not AI-modified1. Analogs of 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin of compound 2
wherein R, R 1 and R 2 independently or in combination represents
R=H or CH 3
R 1 =H or halogen
R 2 =H, NO 2 or halogen.
2. Analogs of 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin as claimed in claim 1 selected from the group consisting of:
S. No
R
R 1
R 2
GI 50 μM
4a
CH 3
H
H
0.04–0.5
4b
H
H
H
15–382
4c
CH 3
2-Cl
4-Cl
0.059–0.876
4d
H
2-Cl
4-Cl
0.1–0.24
4e
CH 3
H
4-NO 2
<10 nM–0.28
4f
H
H
4-NO 2
0.01–0.24
4g
CH 3
H
4-Cl
0.07–1.1
4h
H
H
4-Cl
14–270
4I
CH 3
2-F
4-Cl
0.14–0.3
4j
H
2-F
4-Cl
0.004–0.1
4k
CH 3
H
H
0.1–1
4l
H
H
H
2–16
4m
CH 3
H
4-NO 2
0.01–0.2
4n
H
H
4-NO 2
0.01–0.24
4o
CH 3
H
4-NH 2
0.04–1
4p
H
H
4-NH 2
0.015–0.4 .
3. A process for the preparation of 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin analogs of Compound 2
wherein R, R 1 and R 2 independently or in combination represents
R=H or CH 3
R 1 =H or halogen
R 2 =H, NO 2 or halogen
the process comprising the following steps:
a) reacting 4β-bromo-4-dioxypodophyllotoxin with substituted or unsubstituted 2-aminobenzophenone in presence of phase transfer catalyst, base in an anhydrous organic solvent medium at a temperature ranging between −10° to 40° C. for 4–16 hours,
b) removing the organic solvent from the reaction mixture of step (a) under reduced pressure to obtain a residue, and
c) purifying the residue of step (b) over silica gel column, eluting with mixture of chloroform-methanol to obtain the required 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin analogs.
4. A process as claimed in claim 3 wherein in step (a), the phase transfer catalyst used is selected from a group consisting of tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetra butyl ammonium iodide or aliquat 336.
5. A process as claimed in claim 3 wherein in step (a), the substituted 2-amino benzophenone are selected from group consisting of 2-amino-2′, 5′-dichlorobenzophenone, 2-amino-5-nitrobenzophenone, 2-amino-5-chlorobenzophenone, 2-amino-5-chlorobenzophenone, 2-amino-5-chloro-2′-fluorobenzophenone, 2-amino-4′bromobenzophenone, and 4-amino-3-nitrobenzophenone.
6. A process as claimed in claim 3 wherein in step (a), the organic solvent used is selected from group consisting of dichlorormethane, chloroform, tetrahydrofuran or dioxane.
7. A process as claimed in claim 3 wherein in step (a), the base used is selected from group consisting of trimethylamine, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate and barium carbonate.
8. A process as claimed in claim 3 wherein the reaction is carried out at room temperature.
9. A process as claimed in claim 3 wherein in step (a), the molar ratio of substituted or unsubstituted benzophenone and the bromocompound used is in the range of 1:1 to 2:1 and preferably 1:1.17.
10. A process as claimed in claim 3 wherein in step (a), the mole equivalent ratio of bromo compound to phase transfer catalyst is in the range of 1:0.2 to 1:0.5.
11. A method for treating cancer in a subject in need thereof comprising administering a pharmaceutically effective dosage of 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin analogues of general formula (2) as claimed in claim 1 .
12. A method as claimed in claim 11 wherein 4β-1″-[{2″-benzoyl substituted}anilino] podophyllotoxin analogs are used singly or in combination with each other.
13. A method as claimed in claim 11 wherein the analogs of general formula (2) are administered systemically or orally.
14. A method as claimed in claim 11 wherein the subject is a mammal.
15. A method as claimed in claim 14 wherein the subject is a human.
16. A method as claimed in claim 11 , wherein the compound of general formula (2) is administered to the subject in combination with pharmaceutically acceptable additives, carriers, diluent, solvent, filter, lubricant, excipient, binder or stabilizer.
17. A method as claimed in claim 11 wherein the GI 50 value of in vitro anti-cancer activity of preferred analogs is in the range of 0.001–382.
18. A process as claimed in claim 4 , wherein the phase transfer catalyst is tetrabutylammonium iodide.
19. A process as claimed in claim 7 , wherein the organic solvent is tetrahydrofuran.
20. A process as claimed in claim 8 , wherein the base is triethylamine.
21. A process as claimed in claim 9 , wherein the molar ratio is 1:1.17.Cited by (0)
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